THE RELATIONSHIP BETWEEN CONFORMATION AND BIOLOGICAL-ACTIVITY OF 8-SUBSTITUTED ANALOGS OF 2',5'-OLIGOADENYLATES

Analogues of the 2',5'-linked adenylate trimer 5'-monophosphates, p5'A2'p5'A2'p5'A (pA3) (1a), containing 8-hydroxyadenosine and 8-mercaptoadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. The oligomer, p5'A(SH)2'p5'A(SH)2,p5'A(SH) (pA(SH)3) (1c) had little capacity to bind to RNase L. On the other hand, an analogue of the p5'A(OH)2'p5'A(OH)2'p5'A(OH) (pA(OH)3) (1b) bound almost as well as the parent 2-5A [pppA(2'p5'A)2] (p3A3) (1d) to RNase L. The 8-substituted analogues of 2-5A were more resistant to degradation by (2',5') phosphodiesterase. Finally, the monophosphate, pA(SH)3 (1c) which possessed higher anti-HIV activity than pA3 (1a) or pA(OH)3 (1b).